Approach Considerations

As with all complications of diabetes, successful management of macular edema requires good control of the diabetes itself.

The Early Treatment Diabetic Retinopathy Study (ETDRS) was the first study to provide a treatment paradigm in this disease using laser therapy to reduce moderate vision loss in patients with clinically significant macular edema by approximately 50%.
[9] Although prevention of vision loss is important, visual improvement would be preferable.

Over the past few years, research has started to focus on the use to anti–vascular endothelial growth factor (VEGF) therapy to treat diabetic macular edema (DME). As new and promising treatment options emerge and prospective data begin to mount, it is becoming clearer that anti-VEGF therapy will play an increasing role in the treatment of DME.

A variety of intravitreal medications are currently available, with others under study. Pars plana vitrectomy may also be beneficial.

Medical treatment should focus on optimizing glycemic and hypertensive control and lowering lipid levels. Optimal control of diabetes, blood pressure, and lipids has been shown to positively impact diabetic retinopathy.
[10] These issues are best managed by primary care physicians and internists.

Patients should be counseled about the risk (30-40%) of increased intraocular pressure, which usually can be medically controlled. Other adverse effects include a less than 1% chance of retinal detachment, cataract, and endophthalmitis.

Dexamethasone

In July 2014, the FDA approved dexamethasone intravitreal implant (Ozurdex) for diabetic macular edema in patients who are pseudophakic or are phakic and scheduled for cataract surgery.
[12] This indication was expanded to include the general DME patient population in September 2014.
[13] Approval was based on 2 randomized, multicenter, masked, placebo-controlled, phase III clinical trials with identical protocols. Data from 1048 patients were pooled for analysis. The percentage of patients with ≥15-letter improvement in best-corrected visual acuity (BCVA) from baseline was greater with dexamethasone intravitreal implant 0.7 mg (22.2%) than with placebo implant (12%).
[14]

Fluocinolone acetonide

A long-acting fluocinolone intravitreal implant (Iluvien) was approved by the FDA in September 2014 for the treatment of diabetic macular edema in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. Iluvien consists of tiny, cylindrical tube containing fluocinolone acetonide that is implanted in the back of the eye via a 25-gauge needle and that releases submicrogram levels of the drug for 36 months. Possible adverse reactions to the implant include increased ocular pressure and cataract development.
[15]

Approval was based on clinical trial data from the Fluocinolone Acetonide for Macular Edema (FAME) studies that showed that, at month 24 after receiving the fluocinolone implant (releases 0.2 mcg/day), 28.7% of patients (P = 0.002) experienced an improvement from baseline in their best corrected visual acuity of 15 letters or more on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart. Patients treated with the implant experienced a statistically significant improvement in visual acuity compared to the control group by week 3 of follow-up and maintained a statistically significant advantage over the control through completion of the trial at month 36.
[16]

Intravitreal anti-VEGF agents

Vascular endothelial growth factor (VEGF) increases retinal vascular permeability, causes breakdown of the blood-retina barrier, and results in retina edema. VEGF is up-regulated in diabetic retinopathy. Currently available anti-VEGF agents in the United States include pegaptanib sodium, ranibizumab, aflibercept, and bevacizumab. Bevacizumab is not commercially available as an intravitreal injection.

Pegaptanib sodium is a pegylated aptamer directed against the VEGF-A165 isoform. It was the first FDA-approved ophthalmologic anti-VEGF agent for the treatment of choroidal neovascularization (CNV) from age-related macular degeneration (ARMD). In a phase 2 prospective clinical trial, it appeared to improve anatomic and visual outcome in patients with diabetic macular edema.
[17] Phase 3 trials of pegaptanib sodium for diabetic macular edema are being conducted.

Ranibizumab is a recombinant humanized antibody fragment that is active against all isoforms of VEGF-A. Intravitreal ranibizumab is FDA approved for the treatment of exudative ARMD. In the RESOLVE study (phase 2, placebo-controlled, randomized, multicenter study), 151 patients were randomized 1:1:1 to ranibizumab monotherapy at a dose of 0.3 mg or 0.5 mg or sham treatment. Rescue laser photocoagulation treatment was offered with persistent disease activity after 3 months. Patients received an initial treatment of 3 consecutive monthly injections and were followed monthly with an as-necessary regimen from month 3 to month 12. At month 12, a mean increase in best corrected visual acuity (BCVA) of 11.8 letters in the 0.3-mg group and of 8.8 letters in the 0.5-mg group was noted, as compared with a reduction in BCVA of -1.4 letters in the sham group.
[18]

In the READ-2 study (phase 2, randomized multicenter study), 126 patients were randomized 1:1:1 to receive 0.5 mg of ranibizumab, focal/grid laser coagulation, or a combination of ranibizumab and laser. At month 6, the mean gain in BCVA was significantly greater in the ranibizumab monotherapy group, with +7.2 letters, compared with the laser monotherapy group, who lost -0.4 letters and the combination treatment group, gaining only +3.8 letters.
[19]

In the RESTORE study (phase 3, laser-controlled, randomized, multicenter study), 345 patients were randomized 1:1:1 to 0.5 mg ranibizumab plus sham laser, 0.5 mg ranibizumab plus active laser, or sham injections with active laser. A treatment initiation phase included 3 consecutive monthly intravitreal injections of either ranibizumab or sham. Subsequently, an as-necessary regimen was followed from month 3 to month 12. The mean change in BCVA from baseline to months 1-12 was +6.1 letters in the ranibizumab monotherapy group, +5.9 letters in the group receiving combination therapy with ranibizumab and laser, and +0.8 letters in the laser alone group.
[20]

Three-year results of this trial were reported in 2012,suggestingthatfocal/grid laser treatment at the initiation of intravitreal ranibizumab is not better, and may be worse, for vision outcomes than deferring laser treatment for at least 24 weeks in patients with DME involving the fovea and with vision impairment.
[23]

More patients who received ranibizumab were able to read at least 3 additional lines (15 letters) on the eye chart at 24 months (RIDE, 34% in the 0.3-mg group vs 12% in the control group; RISE, 45% in the 0.3-mg group vs 18% in the control group)

The ranibizumab group had average vision gains exceeding 2 lines (10 letters) on the eye chart at 24 months (RIDE, 10.9 letters in the 0.3-mg group vs 2.3 letters in the control group; RISE, 12.5 letters in the 0.3-mg group vs 2.6 letters in the control group)

Significant gains in average vision were observed 7 days after the first treatment

The ranibizumab group was significantly more likely to maintain their vision (lose < 15 letters on the eye chart) at 24 months (RIDE, 98% in the 0.3-mg group vs 92% in the control group; RISE, 98% in the 0.3-mg group vs 90% in the control group)

Vision improvements observed with ranibizumab treatment at 24 months were maintained with continued treatment through 36 months

The FDA approved aflibercept for diabetic macular edema in August 2014. It was previously approved for neovascular age-related macular degeneration and macular edema. Approval for DME was based on 2 studies (VISTADME and VIVIDDME) comparing aflibercept with macular laser photocoagulation, in which patients treated with aflibercept were able to read, on average, 2 additional lines on an eye chart, while control patients showed no improvement.
[25]

Bevacizumab is a full-length recombinant humanized antibody that is active against all isoforms of VEGF-A. It is FDA approved as an adjunctive systemic treatment for metastatic colorectal cancer. Small, nonrandomized pilot studies have documented some efficacy against diffuse diabetic macular edema. The Diabetic Retinopathy Clinical Research Network conducted a phase 2, prospective, randomized, multicenter clinical trial to determine the safety and possible benefits of this agent. They concluded that intravitreal bevacizumab can reduce diabetic macular edema in some eyes, but the study was not designed to determine whether the treatment was beneficial.
[17] A phase 3 trial would be needed for that purpose.

The intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT) study also recently released 12-month data. This is a prospective, single-center, randomized, 2-year trial, enrolling 80 patients with center-involving clinically significant macular edema (CSME) who had received at least 1 prior macular laser treatment, to compare the efficacy of repeated intravitreal bevacizumab with 4 monthly modified macular laser treatments. The mean change in ETDRS visual acuity at 12 months in the laser group was -0.5 letters, while the bevacizumab group gained a mean of 8 letters during the same period.
[26] At 24 months the mean change in ETDRS visual acuity was a gain of 8.6 letters for the bevacizumab group compared to a mean loss of 0.5 letters for the macular laser therapy group.
[27]

In 2015, the Diabetic Retinopathy Clinical Research Network reported the results of a randomized clinical trial to compare relative changes in visual acuity following 1 year of intravitreal injections of anti-VEGF agents aflibercept, bevacizumab, and ranibizumab for the treatment of diabetic macular edema involving the center of the macula. The mean change in visual acuity at 1 year was greater with aflibercept (+13.3) than bevacizumab (+9.7) or ranibizumab (+11.2). However, this was not clinically significant. The greater overall effect was driven by eyes with initial visual acuity of 20/50 or worse. Mean visual acuity letter score improvement in this subgroup was +18.9 for aflibercept, +11.8 for bevacizumab, and +14.2 for ranibizumab (P values: aflibercept-bevacizumab, <0.001; aflibercept-ranibizumab = 0.003; ranibizumab-bevacizumab = 0.21). For eyes with and initial visual acuity of 20/32 to 20/40, the mean change was +8.0 for aflibercept, +7.5 for bevacizumab, and +8.3 for ranibizumab (P values: >0.50 for each pairwise comparison). In conclusion, in eyes with decreased visual acuity due to diabetic macular edema, all 3 agents, on average, substantially improved VA. However, the relative effect depends on initial visual acuity. When initial visual acuity loss was mild, there was no apparent differences among the 3 treatment groups. However, the worse the initial visual acuity, the greater the relative advantage of aflibercept over the other two agents.
[28]

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Laser Treatments

Laser photocoagulation is a well-proven therapy to reduce the risk of vision loss from diabetic macular edema. The Diabetic Retinopathy Clinical Research Network reported results from a multicenter, randomized clinical trial comparing focal/grid laser photocoagulation and intravitreal triamcinolone for the treatment of diabetic macular edema. They concluded that over a 2-year period, focal/grid laser photocoagulation is more effective and has fewer adverse effects than 1- or 4-mg doses of preservative-free intravitreal triamcinolone for most patients with diabetic macular edema.
[29]

Studies on all other surgical modalities have been limited in the number of patients and the scope of disease being treated; therefore, these procedures have limited use and questionable efficacy.

The goal of macular laser treatment is to reduce progression of diabetic macular edema; significant visual improvement is uncommon. Photocoagulation has been shown to reduce the risk of moderate visual loss from diabetic macular edema by 50%, from 24% to 12%, 3 years after initiation of treatment.
[9]

Laser treatment is most effective when initiated before visual acuity is lost from diabetic macular edema; this emphasizes the need for diligent monitoring and follow-up care.

Laser treatment of diabetic macular edema should precede panretinal photocoagulation (PRP) by at least 6 weeks because the use of PRP before laser treatment may worsen diabetic macular edema. PRP should not be delayed in patients with very severe nonproliferative diabetic retinopathy or high-risk proliferative diabetic retinopathy.

Focal leaks greater than 500 µm from the foveal center that are believed to cause retinal thickening or hard exudates

Focal leaks 300-500 µm from the foveal center that are causing retinal thickening and hard exudates and have persisted after a first treatment in a patient with visual acuity of less than 20/40, provided that treatment will not destroy the perifoveal capillary network

Thickened avascular zones, other than the normal foveal avascular zone

It is important to avoid the foveal avascular zone.

Macular thickness and the need for retreatment

In patients with diabetic macular edema, a significant association exists between higher central macular thickness at baseline and the need for at least 3 treatments with a combination of IVTA and laser photocoagulation, according to a study by O’Day et al. In a post-hoc analysis derived from a prospective, randomized, double-blind, placebo-controlled trial (42 patients/42 eyes), the investigators found that half of the study’s patients required 3 or more IVTA/laser treatments, with macular thickness being the only baseline characteristic significantly associated with the number of treatments received.
[30]

Day and colleagues suggested that as a result of requiring more treatments, patients with high baseline thickness may be at greater risk for intraocular pressure increase, progression of cataract, and steroid-associated adverse events.

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Future Therapies

VEGF Trap-Eye is a soluble VEGF receptor fusion protein that binds all forms of VEGF-A and related placental growth factor (PGF). When administered as a single 4 mg intravitreal injection in a phase 1 study, a marked decrease in central retinal thickness and mean macular volume was noted.

Retisert,
[31] a steroid implant (fluocinolone acetonide), was evaluated in patients with diabetic macular edema with good results, but its adverse effect profile was cause for concern (90% of patients developed cataracts, and 40% required glaucoma surgery within 3 y).

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Pars Plana Vitrectomy

Many studies suggest that vitreomacular traction or the vitreous itself may play a role in increased retinal vascular permeability.
[32, 33] Removal of the vitreous or relief of vitreous traction with vitrectomy may, in some patients, be followed by resolution of macular edema and corresponding visual rehabilitation. However, this treatment may be applicable only to a specific subset of eyes with diabetic macular edema.

Patients with refractory clinically significant macular edema (CSME) and a taut posterior hyaloid face who have not responded to macular laser treatment may benefit from a vitrectomy, with possible significant improvement in visual acuity.
[32]

In eyes with diffuse diabetic macular edema without posterior vitreous detachment, vitrectomy with posterior vitreous detachment may be effective in resolving the diabetic macular edema and may lead to an increase in visual acuity.
[33]

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Complications

Adverse effects and complications of laser use are related mostly to either misdirected light or excessive energy, both of which are generally preventable with operator familiarity with standard treatment parameters.

Subretinal fibrosis is a vision-threatening condition, which occurred in 2% of eyes with diabetic macular edema in the Early Treatment Diabetic Retinopathy Study (ETDRS).
[34] Subretinal fibrosis is an elevated mound or flat sheet of grey or white tissue deep to the retina at or near the center of the macula. On fluorescein angiography, this lesion is hyperfluorescent in the capillary phase with persistence into the late phase and diffusion of dye. Subretinal fibrosis is associated most strongly with very severe hard exudates. It also is associated with a poor lipid profile. A previously proposed association with laser treatment has not been demonstrated in studies. The prognosis for patients with this complication is poor; subretinal fibrosis is generally refractive to focal laser therapy.

Residual massive foveal hard exudates may remain after the resolution of diabetic macular edema and may be associated with profound and irreversible vision loss. In one study, aspiration of hard exudates following a small retinotomy and serous neurosensory detachment resulted in an increase of visual acuity in 5 of 7 patients.
[35]

Disclosure: Received honoraria from Novartis for speaking and teaching; Received honoraria from Allergan for review panel membership; Received honoraria from Alcon for review panel membership; Received honoraria from Bayer for consulting; Received honoraria from Alcon for review panel membership; Received honoraria from Novartis for review panel membership.